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Page 8 of 17 Nasr et al. Metab Target Organ Damage 2023;3:19 https://dx.doi.org/10.20517/mtod.2023.20

indicating that lipotoxicity and inflammation lead to metabolic dysregulation associated with insulin
[125]
resistance, a hallmark for hepatic lipid accumulation .
COVID-19 and hepatic steatosis
In December 2019, the emergence of coronavirus disease 2019 (COVID-19), caused by the Severe Acute
Respiratory Syndrome (SARS) Coronavirus (CoV) 2 (SARS-CoV-2), led to a major global health and
[126]
economic crisis . Although the respiratory tract was considered the main target of SARS-CoV-2 infection,
other organs, including the liver, have also been shown to be affected [126,127] .

Elevated liver transaminases in COVID-19 patients are seen in approximately 20% of patients .
[128]
Furthermore, elevated transaminases are often accompanied by elevated cholestatic liver enzymes, probably
reflecting systemic inflammatory response syndrome (SIRS). The cause of elevated liver enzymes can be
directly associated with COVID-19 but is most often multifactorial.

COVID-19-associated liver injury includes a broad spectrum of potential mechanisms of action, such as
active viral replication of SARS-CoV-2 in the liver with subsequent cytotoxicity, liver damage due to SIRS,
respiratory failure with induced hypoxic liver damage, vascular changes due to coagulopathy, endothelial
dysfunction or cardiac congestion from right heart failure, drug-induced liver injury, and exacerbation of
underlying liver disease [129,130] .

So far, information on underlying histopathological alterations is scarce. Hepatic steatosis appears to be
commonly encountered in the livers of patients with SARS-CoV-2 infection, both radiologically and
histopathologically, either alone or together with inflammation [131-134] . To date, more than 20 studies with
histological samples of the liver are present . Most samples are retrieved postmortem and reflect a very
[131]
selected population, and furthermore, most studies are written on available data during autopsy; hence,
clinical data are limited. Nevertheless, histological samples on approximately 270 patients who died
secondary to COVID-19 can be found in the literature, of whom 57% have hepatic steatosis, often mild, and
difficult to distinguish from, e.g., shock/SIRS, drug-induced liver injury, or metabolic syndrome [130,131,134-153] .
In studies where some clinical data is present, the majority of individuals are elderly, and more than a third
have type 2 diabetes and/or are obese, with almost two-thirds having hypertension. This is not surprising
since cardiometabolic risk factors were seen as a risk factor for COVID-19 mortality . Similarly, in
[154]
radiological studies (utilizing either magnetic resonance imaging or computed tomography), hepatic
steatosis seems to be associated with the severity of COVID-19 illness, but is often of collinearity with
obesity, type 2 diabetes, and hypertension [132,133] .

Steatotic liver disease is a common finding in patients with COVID-19. Although COVID-19 does not seem
to have any steatogenic properties, it is unknown if hepatic steatosis is a risk factor for more severe COVID-
19, including increased mortality. Even though the incidence of hepatic steatosis is common in autopsies of
patients who have died secondary to COVID-19, this is probably secondary to co-morbid conditions
associated with increased mortality in COVID-19 (such as obesity and type 2 diabetes).

Environmental toxin-associated steatosis
A wide variety of environmental toxins can induce steatosis and steatohepatitis. Among these are metals
(arsenic, cadmium, lead, mercury), pesticides/fungicides (e.g., fludioxonil, triflumizole), herbicides (e.g.,
dioxin), polychlorinated biphenyls, and chloroalkenes (e.g., perchloroethylene, trichloroethylene, and vinyl
chloride) [155-157] . These agents may induce hepatic fat accumulation but also aggravate pre-existing MASLD.